Thrombin is known to have a variety of activities in different cell types and thrombin receptors are known to be present in such cell types as human platelets, vascular smooth muscle cells, endothelial cells, and fibroblasts. Thrombin receptor antagonists may be useful in the treatment of thrombotic, inflammatory, atherosclerotic and fibroproliferative disorders, as well as other disorders in which thrombin and its receptor play a pathological role. See, for example, U.S. Pat. No. 6,063,847, the disclosure of which is incorporated by reference.
One thrombin receptor antagonist is a compound of the formula and salts thereof:

This compound is an orally bioavailable thrombin receptor antagonist derived from himbacine, and its synthesis proceeds through a Diels-Alder reaction.
Processes for the synthesis of similar himbacine analog thrombin receptor antagonists are disclosed in U.S. Pat. No. 6,063,847, and U.S. publication no. 2004/0216437A1, and the synthesis of the bisulfate salt of a particular himbacine analog is disclosed in U.S. publication no. 2004/0176418A1, the disclosures of which are incorporated by reference herein. The present invention provides an improved process for preparing thrombin receptor antagonists by providing at least one of a higher yield of the desired exo product via the Diels-Alder reaction, a simple and more efficient conversion of amide intermediates to their corresponding carboxylates, and improved purification of intermediates via crystallization.